title: Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial.
abstract: The capsaicin receptor (TRPV1) antagonist ABT-102 demonstrates efficacy in multiple preclinical pain models. However, evolving clinical data for this compound class suggest potentially profound drug-induced thermosensory impairment. Safety and tolerability of ABT-102 were assessed in a multiple-dose, double-blind, placebo-controlled, randomized healthy volunteer trial. Thirty-six participants were randomized in a 2:1 ratio to ABT-102:placebo in 3 dose groups (1 mg, 2 mg, and 4 mg twice a day) and confined to an inpatient research unit for a 7-day treatment period and 3 follow-up days. Outcome measures included: oral and cutaneous cold detection, warm detection (WDT), and heat pain thresholds (HPT); oral perceived heat intensity (oral liquid test); time to hand withdrawal (water bath test); and cutaneous pain intensity (long thermal stimulus). Significant dose-dependent (placebo- and baseline-adjusted) increases in HPT and reduced painfulness of suprathreshold heat were present from days 1-7. For ABT-102 4 mg twice a day, model-based mean differences from placebo (95% confidence interval) were as follows: oral HPT, day 1=2.5°C (0.6-4.4), day 5=4.4°C (2.5-6.3); cutaneous HPT, day 2=3.3°C (1.4-5.3), day 5=5.3°C (3.3-7.2); oral WDT, day 1=2.6°C (0.5-4.7), day 5=2.7°C (0.6-4.9); cutaneous WDT, day 2=1.3 (0.0-2.6), day 5=1.6 (0.3-2.8) (all P<0.05). Oral liquid test and water bath test results followed a similar pattern. There was no effect on cutaneous cold detection. All effects were fully reversed by day 10. There were no other relevant safety findings. Core body temperature remained below 39°C in all participants. In conclusion, ABT-102 potently and reversibly increased HPT and reduced painfulness of suprathreshold oral/cutaneous heat.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, USA Abbott Pain Care, Abbott Park, IL, USA Abbott Neuroscience and Pain Discovery, Abbott Park, IL, USA MINDLab, Center of Functionally Integrative Neuroscience, Aarhus University Hospital & Department of Clinical Oral Physiology, School of Dentistry, Aarhus University, Aarhus C, Denmark.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
authors.forename: Wolfram
authors.initials: W
authors.lastname: Nothaft
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Duan
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Connie
authors.initials: C
authors.lastname: Faltynek
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.forename: Peter
authors.initials: P
authors.lastname: Svensson
mesh_terms: D000005:Abdomen / Q000294:innervation; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects*; D012867:Skin / Q000294:innervation; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013697:Thermosensing / Q000187:drug effects*; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C528492:ABT 102; D007191:Indazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea